Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054, USA.
Cancer Cell. 2012 Feb 14;21(2):196-211. doi: 10.1016/j.ccr.2011.12.025.
Elevated Aurora kinase-A expression is correlated with abrogation of DNA damage-induced apoptotic response and mitotic spindle assembly checkpoint (SAC) override in human tumor cells. We report that Aurora-A phosphorylation of p73 at serine235 abrogates its transactivation function and causes cytoplasmic sequestration in a complex with the chaperon protein mortalin. Aurora-A phosphorylated p73 also facilitates inactivation of SAC through dissociation of the MAD2-CDC20 complex in cells undergoing mitosis. Cells expressing phosphor-mimetic mutant (S235D) of p73 manifest altered growth properties, resistance to cisplatin- induced apoptosis, as well as premature dissociation of the MAD2-CDC20 complex, and accelerated mitotic exit with SAC override in the presence of spindle damage. Elevated cytoplasmic p73 in Aurora-A overexpressing primary human tumors corroborates the experimental findings.
极光激酶-A 表达水平升高与人类肿瘤细胞中 DNA 损伤诱导的凋亡反应和有丝分裂纺锤体装配检查点 (SAC) 失控的消除有关。我们发现极光激酶-A 可使 p73 的丝氨酸 235 磷酸化，从而使其转录激活功能丧失，并与伴侣蛋白 mortalin 形成复合物而发生细胞质隔离。在有丝分裂的细胞中，极光激酶-A 磷酸化的 p73 还可通过 MAD2-CDC20 复合物的解离来促进 SAC 的失活。表达磷酸化模拟突变体（S235D）的 p73 的细胞表现出改变的生长特性、对顺铂诱导的凋亡的抗性，以及 MAD2-CDC20 复合物的过早解离，并在纺锤体损伤的情况下加速有丝分裂的退出和 SAC 失控。在过度表达极光激酶-A 的原发性人肿瘤中，细胞质内 p73 水平升高证实了这些实验结果。
